EP1075534B1 - Verbesserung der enzymatischen synthese von chiralen aminen - Google Patents

Verbesserung der enzymatischen synthese von chiralen aminen Download PDF

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Publication number
EP1075534B1
EP1075534B1 EP99911250A EP99911250A EP1075534B1 EP 1075534 B1 EP1075534 B1 EP 1075534B1 EP 99911250 A EP99911250 A EP 99911250A EP 99911250 A EP99911250 A EP 99911250A EP 1075534 B1 EP1075534 B1 EP 1075534B1
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EP
European Patent Office
Prior art keywords
aminopropane
amino
amine
transaminase
chiral
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
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EP99911250A
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English (en)
French (fr)
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EP1075534A4 (de
EP1075534A1 (de
EP1075534B8 (de
Inventor
Wei Wu
Mohit B. Bhatia
Craig M. Lewis
Wei Lang
Alice Wang
George W. Matcham
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Celgro
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Celgro
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Priority to DK99911250T priority Critical patent/DK1075534T3/da
Priority to SI9930805T priority patent/SI1075534T1/xx
Publication of EP1075534A1 publication Critical patent/EP1075534A1/de
Publication of EP1075534A4 publication Critical patent/EP1075534A4/de
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Publication of EP1075534B1 publication Critical patent/EP1075534B1/de
Publication of EP1075534B8 publication Critical patent/EP1075534B8/de
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/001—Amines; Imines
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/005—Amino acids other than alpha- or beta amino acids, e.g. gamma amino acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/04—Alpha- or beta- amino acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/04—Alpha- or beta- amino acids
    • C12P13/06—Alanine; Leucine; Isoleucine; Serine; Homoserine
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/04—Alpha- or beta- amino acids
    • C12P13/12—Methionine; Cysteine; Cystine
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
    • C12P41/006—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures

Definitions

  • the present invention relates to improvements in the enzymatic synthesis of chiral compounds containing an amino group; e.g., chiral amines.
  • Amino acid transaminases are known pyridoxal phosphate dependent enzymes found in various microorganisms including Pseudomonas, Escherichia, Bacillus, Saccharomyces, Hansenula, Candida, Streptomyces, Aspergillus, and Neurospora.
  • U.S. Patents Nos. 4,950,606, 5,169,780, and 5,300,437 disclose that individual strains of transaminase-containing organisms can be isolated by chemostat culture, that is, culturing in a constant but restricted chemical environment, with an amino acceptor and an amine as the sole nitrogen source.
  • a typical strain thus isolated in the noted patents was characterized (by the American Type Culture Collection) as Bacillus megaterium .
  • achiral (non-chiral) carbon atom Normally omega amino acid transaminases metabolize amino acids in which the amino group is on a terminal, achiral (non-chiral) carbon atom and the amine utilized as the nitrogen source in such a chemostat culture can be of the same type, namely achiral amines such as n-octylamine, cyclohexylamine, 1,4-butanediamine, 1,6-hexanediamine, 6-aminohexanoic acid, 4-aminobutyric acid, tyramine, and benzyl amine.
  • achiral amines such as n-octylamine, cyclohexylamine, 1,4-butanediamine, 1,6-hexanediamine, 6-aminohexanoic acid, 4-aminobutyric acid, tyramine, and benzyl amine.
  • the amine utilized as the nitrogen source in such chemostat cultures can be a chiral amine such as 2-aminobutane, ⁇ -phenethylamine, and 2-amino-4-phenylbutane.
  • Chiral amino acids such as L-lysine, L-ornithine, ⁇ -alanine, and taurine also can be used.
  • U.S. Patents Nos. 4,950,606, 5,169,780, and 5,300,437 disclose the stereoselective synthesis of one chiral form of an amine by the action of an amino acid transaminase on a ketone of the formula R 1 COR 2 , in which R 1 and R 2 are different alkyl or aryl groups, in the presence of an amino donor.
  • the amino donors disclosed are similar to the amines used as the nitrogen source in the chemostat cultures; e.g.
  • achiral amines in which the amino group is on a terminal carbon atom such a propyl amine and benzyl amine
  • chiral amines in which the amino group is on a terminal carbon atom such as (S)-2-aminobutane
  • chiral amino acids such as L-alanine and L-aspartic acid.
  • the present invention is based on the discovery that the achiral amine 2-aminopropane is unexpectedly superior as an amine donor in such transaminase amine syntheses as compared with either achiral amines in which the amino group is on a terminal carbon atom or chiral amines in which the amino group is on a nonterminal carbon atom.
  • the invention thus constitutes the improvement in-the known stereoselective synthesis of a chiral amine in which a ketone is brought into contact with a transaminase in the presence of an amino donor, of utilizing 2-aminopropane as the amine donor.
  • chiral amine is employed herein in its broadest sense.
  • the known stereospecific synthesis can be applied to the preparation of a wide variety of aliphatic and alicyclic compounds of different, and mixed, functional types, characterized only by the presence of a primary amino group bound to a secondary carbon atom which, in addition to a hydrogen atom, carries either (i) a divalent group forming a chiral cyclic structure, or (ii) two substituents (other than hydrogen) differing from each other in structure or chirality.
  • Divalent groups forming a chiral cyclic structure include for example 2-methylbutane-1,4-diyl, pentane-1,4-diyl, hexane-1,4-diyl, hexane-1,5-diyl, 2-methylpentane-1,5-diyl.
  • 2-aminopropane as the amine donor can be used in the stereospecific synthesis of 1-amino-2-methylcyclopentane from 2-methylcyclopentanone, 1-amino-3-methylcyclopentane from 3-methylcyclopentanone, 1-amino-2-methylcyclohexane from 2-methylcyclohexanone, etc.
  • the two different substituents on the secondary carbon atom also can vary widely and include alkyl, aralkyl, aryl, halo, hydroxy, lower alkyl, lower alkoxy, lower alkylthio, cycloalkyl, carboxy, cabalkoxy, carbamoyl, mono- and di-(lower alkyl) substituted carbamoyl, trifluoromethyl, phenyl, nitro, amino, mono- and di-(lower alkyl) substituted amino, alkylsulfonyl, arylsulfonyl, alkylcarboxamido, arylcarboxamido, etc., as well as alkyl, aralkyl, or aryl substituted by the foregoing.
  • 2-aminopropane as the amine donor also can be used in the stereospecific synthesis of 2-aminobutane from butanone, 2-amino-1-butanol from 1-hydroxybutan-2-one, alanine from pyruvic acid, 1-amino-1-phenylethane from acetophenone, 1-amino-1-(2-methoxy-5-fluorophenyl)ethane from 2-methoxy-5-fluoroacetophenone, ⁇ -amino-pentanoic acid from levulinic acid, 1-amino-1-phenylpropane from 1-phenylpropan-1-one, 1-amino-1-(4-bromophenyl)propane from 1-(4-bromophenyl)propan-1-one, 1-amino-1-(4-nitrophenyl)-propane from 1-(4-nitrophenyl)propan-1-one, 1-phenyl-2-aminopropane from
  • 2-aminopropane In contrast to the amine donors reported in the prior art, and indeed the majority of aminoalkane amino donors which are theoretically available, 2-aminopropane possesses the relatively unique combination of (i) being achiral and (ii) having the amino group on a non-terminal aliphatic carbon atom. Thus notwithstanding the use of an omega-amino acid transaminase, which in nature acts on an amino group in the terminal or ⁇ -position of an amino acid, it has been found that the use as an amino donor having an amino group on a non-terminal aliphatic carbon atom affords a thermodynamic advantage.
  • thermodynamic advantage of using isopropylamine as the amino donor results in an equilibrium constant of approximately 1,000. Because this thermodynamic advantage stems from the chemical environment of the reacting carbonyl group, this applies equally to the synthesis of all chiral ⁇ -amino acids from their ketoacids, whether natural or unnatural.
  • the actual enzymatic conversion can be effected by conventional culturing techniques with isolated but non-growing cells, or with a soluble amino acid transaminase preparation.
  • the amino acid transaminase can be in free form, either as a cell free extract or a whole cell preparation, or immobilized on a suitable support or matrix such as cross-linked dextran or agarose, silica, polyamide, or cellulose. It also can be encapsulated in polyacrylamide, alginates, fibers, or the like. Methods for such immobilization are described in the literature (see, for example, Methods of Enzymology , 44, 1976).
  • a source of pyridoxamine such as pyridoxal phosphate.
  • the invention can be exemplified by the preparation of (S)-1-methoxy-2-aminopropane, a chemical intermediate for the synthesis of agricultural chemicals, in which methoxyacetone is brought into contact with a transaminase in the presence of 2-aminopropane as an amine donor, permitting the reaction to continue until a substantial amount of methoxyacetone is converted to (S)-1-methoxy-2-aminopropane (and 2-aminopropane is simultaneously converted to acetone), and isolating the (S)1-methoxy-2-aminopropane thus formed.
  • the overall enzymatic transformation can be depicted as follows:
  • the enzyme solution was prepared separately. To 200 mL of 5 mM of sodium phosphate solution (pH 7.5), 0.2 mM of pyridoxal 5'-phosphate and 2g (dry weight) of Bacillus cells, containing an (S)-transaminase were added. When the cells were completely suspended, the enzyme solution was delivered into the reaction mixture described above.
  • the final reaction broth contained 1.5 M of 2-aminopropane and 1.0M of methoxyacetone.
  • the reaction proceeded for 8 hours at 30 ⁇ 1°C and pH 7.5, at which point (S)-1-methoxy-2-aminopropane was present in the reaction mixture at a concentration of 0.6M with an ee of greater than 99%.
  • the reaction was terminated by the addition of 5 mL of concentrated hydrochloric acid, followed by flash distillation to remove unreacted methoxyacetone and the by-product, acetone, in a single cut. A separate column distillation of this distillate late can be conducted subsequently to separate the methoxyacetone and acetone. Two hundred and seventy milliliters of 50% aqueous sodium hydroxide were added to the reaction mixture to deprotonate the amines.
  • the invention can be further exemplified by the synthesis of L-alanine, a useful amino acid, in which pyruvic acid is brought into contact with a transaminase in the presence of 2-aminopropane as an amino donor, permitting the reaction to continue until a substantial amount of pyruvic add is converted to L-alanine and 2-aminopropane is simultaneously converted to acetone.
  • the overall enzymatic transformation can be depicted as follows:

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Claims (3)

  1. Stereoselektive Synthese eines chiralen Amins, bei dem man ein Keton in Gegenwart eines Aminogruppendonators mit einer Transaminase in Berührung bringt, dadurch gekennzeichnet, daß man als Aminogruppendonator 2-Aminopropan verwendet.
  2. Synthese nach Anspruch 1, bei der es sich bei dem chiralen Amin um eine chirale Aminosäure handelt.
  3. Verfahren zur Herstellung von (S)-1-Methoxy-2-aminopropan, bei dem man Methoxyaceton in Gegenwart von 2-Aminopropan als Aminogruppendonator mit einer Transaminase in Berührung bringt, bis eine wesentliche Menge von Methoxyaceton in (S)-1-Methoxy-2-aminopropan und 2-Aminopropan in Aceton umgewandelt ist, und das (S)-1-Methoxy-2-aminopropan isoliert.
EP99911250A 1998-03-11 1999-03-10 Verbesserung der enzymatischen synthese von chiralen aminen Expired - Lifetime EP1075534B8 (de)

Priority Applications (2)

Application Number Priority Date Filing Date Title
DK99911250T DK1075534T3 (da) 1998-03-11 1999-03-10 Forbedringer af den enzymatiske syntese af chirale aminer
SI9930805T SI1075534T1 (en) 1998-03-11 1999-03-10 Improvements in the enzymatic synthesis of chiral amines

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US7752098P 1998-03-11 1998-03-11
US77520P 1998-03-11
PCT/US1999/005150 WO1999046398A1 (en) 1998-03-11 1999-03-10 Improvements in the enzymatic synthesis of chiral amines

Publications (4)

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EP1075534A1 EP1075534A1 (de) 2001-02-14
EP1075534A4 EP1075534A4 (de) 2003-07-09
EP1075534B1 true EP1075534B1 (de) 2005-05-11
EP1075534B8 EP1075534B8 (de) 2005-07-06

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EP99911250A Expired - Lifetime EP1075534B8 (de) 1998-03-11 1999-03-10 Verbesserung der enzymatischen synthese von chiralen aminen

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EP (1) EP1075534B8 (de)
JP (1) JP2002505884A (de)
KR (1) KR20010034561A (de)
CN (1) CN1154746C (de)
AT (1) ATE295424T1 (de)
AU (1) AU753904B2 (de)
BR (1) BR9908797A (de)
CA (1) CA2322605A1 (de)
CZ (1) CZ295882B6 (de)
DE (1) DE69925267T2 (de)
ES (1) ES2243051T3 (de)
FI (1) FI20001805A (de)
HK (1) HK1035000A1 (de)
HU (1) HUP0101056A3 (de)
MX (1) MXPA00008573A (de)
NO (1) NO319671B1 (de)
NZ (1) NZ506405A (de)
PL (1) PL342882A1 (de)
PT (1) PT1075534E (de)
RU (1) RU2213142C2 (de)
SK (1) SK284352B6 (de)
TR (1) TR200002604T2 (de)
UA (1) UA64784C2 (de)
WO (1) WO1999046398A1 (de)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8293507B2 (en) 2009-02-26 2012-10-23 Codexis, Inc. Transaminase biocatalysts
US8921079B2 (en) 2009-06-22 2014-12-30 Codexis, Inc. Transaminase reactions
US8932836B2 (en) 2010-08-16 2015-01-13 Codexis, Inc. Biocatalysts and methods for the synthesis of (1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexanamine

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE60013939T2 (de) 1999-03-19 2005-10-06 Sumitomo Chemical Co. Ltd. Stereoselektive Transaminase, deren kodierende Gen und deren Verwendungen
JP2001190298A (ja) * 2000-01-13 2001-07-17 Kanegafuchi Chem Ind Co Ltd 光学活性ｎ−メチルアミノ酸の製造方法
EP1818411A1 (de) * 2006-02-13 2007-08-15 Lonza AG Verfahren zur Herstellung von optisch aktiven chiralen Aminen
DE102007042600A1 (de) 2007-09-07 2009-03-12 Evonik Degussa Gmbh Verfahren zur Herstellung von enantiomerenangereichten Aminen
DK3354727T3 (da) 2009-01-08 2020-11-16 Codexis Inc Transaminasepolypeptider
EP2857505B1 (de) * 2009-09-02 2016-10-19 Lonza AG Verfahren zur Identifikation und Herstellung von (R)-spezifischer Omega-Transaminase
US8852900B2 (en) 2010-06-17 2014-10-07 Codexis, Inc. Biocatalysts and methods for the synthesis of (S)-3-(1-aminoethyl)-phenol
JP6275642B2 (ja) * 2011-08-16 2018-02-07 エンバイオ・リミテツド 光学活性キラルアミンの酵素的合成
CN104630170A (zh) * 2013-11-08 2015-05-20 中国科学院天津工业生物技术研究所 一种来源于里氏木霉的新(r)-转氨酶及其应用
CN114134126B (zh) * 2021-10-28 2023-12-05 浙江大学杭州国际科创中心 转氨酶及其突变体在制备(s)-1-甲氧基-2-丙胺中的应用

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5300437A (en) * 1989-06-22 1994-04-05 Celgene Corporation Enantiomeric enrichment and stereoselective synthesis of chiral amines
DE69635082T2 (de) * 1995-10-23 2006-06-01 Kaneka Corp. Verfahren zur herstellung optisch aktiver aminoverbindungen

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8293507B2 (en) 2009-02-26 2012-10-23 Codexis, Inc. Transaminase biocatalysts
US8889380B2 (en) 2009-02-26 2014-11-18 Codexis, Inc. Transaminase biocatalysts
US11078505B2 (en) 2009-02-26 2021-08-03 Codexis, Inc. Transaminase biocatalysts
US10619176B2 (en) 2009-02-26 2020-04-14 Codexis, Inc. Transaminase biocatalysts
US9133445B2 (en) 2009-02-26 2015-09-15 Codexis, Inc. Transaminase biocatalysts
US9353355B2 (en) 2009-02-26 2016-05-31 Codexis, Inc. Transaminase biocatalysts
US10160985B2 (en) 2009-02-26 2018-12-25 Codexis, Inc. Transaminase biocatalysts
US9550982B2 (en) 2009-02-26 2017-01-24 Codexis, Inc. Transaminase biocatalysts
US9944963B2 (en) 2009-02-26 2018-04-17 Codexis, Inc. Transaminase biocatalysts
US10138503B2 (en) 2009-06-22 2018-11-27 Codexis, Inc. Transaminase reactions
US9434968B2 (en) 2009-06-22 2016-09-06 Codexis, Inc. Transaminase reactions
US10767202B2 (en) 2009-06-22 2020-09-08 Codexis, Inc. Transaminase reactions
US8921079B2 (en) 2009-06-22 2014-12-30 Codexis, Inc. Transaminase reactions
US11371067B2 (en) 2009-06-22 2022-06-28 Codexis, Inc. Transaminase reactions
US8932836B2 (en) 2010-08-16 2015-01-13 Codexis, Inc. Biocatalysts and methods for the synthesis of (1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexanamine

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PL342882A1 (en) 2001-07-16
PT1075534E (pt) 2005-09-30
EP1075534A4 (de) 2003-07-09
FI20001805A (fi) 2000-08-15
NO20004036L (no) 2000-10-27
NZ506405A (en) 2003-08-29
TR200002604T2 (tr) 2000-11-21
DE69925267D1 (de) 2005-06-16
NO319671B1 (no) 2005-09-05
BR9908797A (pt) 2000-12-12
EP1075534A1 (de) 2001-02-14
NO20004036D0 (no) 2000-08-11
EP1075534B8 (de) 2005-07-06
ATE295424T1 (de) 2005-05-15
SK13382000A3 (sk) 2001-05-10
HUP0101056A3 (en) 2006-03-28
ES2243051T3 (es) 2005-11-16
RU2213142C2 (ru) 2003-09-27
SK284352B6 (sk) 2005-02-04
HK1035000A1 (en) 2001-11-09
AU2993899A (en) 1999-09-27
MXPA00008573A (es) 2003-07-14
DE69925267T2 (de) 2006-01-26
AU753904B2 (en) 2002-10-31
CN1292828A (zh) 2001-04-25
HUP0101056A2 (hu) 2001-07-30
UA64784C2 (en) 2004-03-15
CZ295882B6 (cs) 2005-11-16
CZ20003177A3 (cs) 2000-12-13
CN1154746C (zh) 2004-06-23
WO1999046398A1 (en) 1999-09-16
KR20010034561A (ko) 2001-04-25
CA2322605A1 (en) 1999-09-16
JP2002505884A (ja) 2002-02-26

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